Hemodynamic shear stress and its role in atherosclerosis.

doi:10.1001/JAMA.282.21.2035

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Hemodynamic shear stress and its role in atherosclerosis.

Journal Article•DOI•

Hemodynamic shear stress and its role in atherosclerosis.

Adel M. Malek¹, Seth L. Alper, Seigo Izumo•Institutions (1)

Brigham and Women's Hospital¹

01 Dec 1999-JAMA (American Medical Association)-Vol. 282, Iss: 21, pp 2035-2042

TL;DR: The functional regulation of the endothelium by local hemodynamic shear stress provides a model for understanding the focal propensity of atherosclerosis in the setting of systemic factors and may help guide future therapeutic strategies.

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Abstract: Atherosclerosis, the leading cause of death in the developed world and nearly the leading cause in the developing world, is associated with systemic risk factors including hypertension, smoking, hyperlipidemia, and diabetes mellitus, among others. Nonetheless, atherosclerosis remains a geometrically focal disease, preferentially affecting the outer edges of vessel bifurcations. In these predisposed areas, hemodynamic shear stress, the frictional force acting on the endothelial cell surface as a result of blood flow, is weaker than in protected regions. Studies have identified hemodynamic shear stress as an important determinant of endothelial function and phenotype. Arterial-level shear stress (>15 dyne/cm2) induces endothelial quiescence and an atheroprotective gene expression profile, while low shear stress (<4 dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates an atherogenic phenotype. The functional regulation of the endothelium by local hemodynamic shear stress provides a model for understanding the focal propensity of atherosclerosis in the setting of systemic factors and may help guide future therapeutic strategies.

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Journal Article•

ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).

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Elliott M. Antman, Daniel T. Anbe, Paul W. Armstrong, Eric R. Bates¹, Lee A. Green, Mary M. Hand, Judith S. Hochman, Harlan M. Krumholz, Frederick G. Kushner, Gervasio A. Lamas, Charles J. Mullany, Joseph P. Ornato, David L. Pearle, Michael A. Sloan, Sidney C. Smith, Joseph S. Alpert, Jeffrey L. Anderson, David P. Faxon, Valentin Fuster, Raymond J. Gibbons, Gabriel Gregoratos, Jonathan L. Halperin, Loren F. Hiratzka, Sharon A. Hunt, Alice K. Jacobs - Show less +21 more•Institutions (1)

University of Michigan¹

01 Aug 2004-Canadian Journal of Cardiology

TL;DR: Elliott M. Antman,MD, FACC, FAHA, Chair; Daniel T. Anbe, MD, F ACC,FAHA; Paul Wayne Armstrong, MD; Eric R. Bates; Lee A. Green; Mary Hand; Judith S. Kushner; and Sidney C. Sloan.

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7,134 citations

Cites background from "Hemodynamic shear stress and its ro..."

...Plaques that are prone to disruption are usually nonobstructive, are characterized by abundant macrophages and other inflammatory cells, and are often located at branch points or bends in the arterial tree (11-15)....
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Journal Article•DOI•

ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction

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Elliott M. Antman, Daniel T. Anbe, Paul W. Armstrong, Eric R. Bates, Lee A. Green, Mary M. Hand, Judith S. Hochman, Harlan M. Krumholz, Frederick G. Kushner, Gervasio A. Lamas, Charles J. Mullany, Joseph P. Ornato, David L. Pearle, Michael A. Sloan, Sidney C. Smith, Joseph S. Alpert, Jeffrey L. Anderson, David P. Faxon, Valentin Fuster, Raymond J. Gibbons, Gabriel Gregoratos, Jonathan L. Halperin, Loren F. Hiratzka, Sharon A. Hunt, Alice K. Jacobs - Show less +21 more

01 Aug 2004-Journal of the American College of Cardiology

TL;DR: This document was approved by the American College of Cardiology Foundation Board of Trustees on May 7, 2004 and by theAmerican Heart Association Science Advisory and Coordinating Committee on May 5, 2004.

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1,846 citations

Cites background from "Hemodynamic shear stress and its ro..."

...Plaques that are prone to disruption are usually nonobstructive, are characterized by abundant macrophages and other inflammatory cells, and are often located at branch points or bends in the arterial tree (11-15)....
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Journal Article•DOI•

Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis

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Michael A. Gimbrone¹, Guillermo García-Cardeña¹•Institutions (1)

Brigham and Women's Hospital¹

19 Feb 2016-Circulation Research

TL;DR: This review traces the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explores its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerosis.

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Abstract: Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell dysfunction, in its broadest sense, encompasses a constellation of various nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone and redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. In this review, we trace the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explore its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerotic cardiovascular disease; consider current approaches to the clinical assessment of endothelial cell dysfunction; and outline some promising new directions for its early detection and treatment.

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1,811 citations

Journal Article•DOI•

Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives

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Jeng Jiann Chiu¹, Shu Chien•Institutions (1)

National Health Research Institutes¹

01 Jan 2011-Physiological Reviews

TL;DR: Current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications are summarized to contribute to the understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.

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Abstract: Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.

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1,699 citations

Cites background or methods from "Hemodynamic shear stress and its ro..."

...geometries at arterial branch points, curvatures, and poststenotic regions lead to disturbances in flow pattern, with a low net forward flow and shear stress ( 4 dyn/cm(2)), such complex flow patterns without a clear direction play significant roles in inducing endothelial dysfunction, with impairment of NO production (93, 103, 213, 360, 545, 571)....
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...The pulsatile flow in the straight part of the arterial tree is laminar with high shear stresses (10–70 dyn/cm(2)) (208, 214, 360)....
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...Experimental measurements using different methods have shown that in humans the magnitude of shear stress ranges from 1 to 6 dyn/cm(2) in the venous system and from 10 to 70 dyn/cm(2) in arteries (85, 360, 417)....
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...The net effect of these endothelium-mediated compensatory responses is the maintenance of mean shear stress of the arterial system at 15–20 dyn/cm(2) (208, 214, 360)....
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...While certain types of hemodynamic forces are essential for physiological functions of the EC under normal conditions, other types can induce endothelial dysfunction by adversely modulating EC signaling and gene expression, thus contributing to the development of vascular pathologies (42, 87, 93, 212, 213, 337, 360, 416, 451, 485, 571, 625), in concert with the risk factors that act on the entire arterial system (e....
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Journal Article•DOI•

Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.

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Yiannis S. Chatzizisis¹, Ahmet U. Coskun², Michael Jonas³, Elazer R. Edelman³, Elazer R. Edelman¹, Charles L. Feldman¹, Peter Stone¹ - Show less +3 more•Institutions (3)

Brigham and Women's Hospital¹, Northeastern University², Massachusetts Institute of Technology³

26 Jun 2007-Journal of the American College of Cardiology

TL;DR: The molecular, cellular, and vascular processes supporting the role of low ESS in the natural history of coronary atherosclerosis and vascular remodeling are explored and likely mechanisms concerning the different natural history trajectories of individual coronary lesions are indicated.

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1,350 citations

Cites background from "Hemodynamic shear stress and its ro..."

...Low SS increases MMPs expression by ECs through activation f these TFs....
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...ow ESS refers to ESS that is unidirectional at any given oint but has a periodically fluctuating magnitude that esults in a significantly low time-average (approximately 10 to 12 dyne/cm(2)) (4,6,15) (Fig....
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...The BMP-4 stimulates the expression and ctivity of NADPH oxidase, thereby leading to ROS roduction, NF- B activation, pro-inflammatory cytokine xpression, and subsequent increased monocyte adhesivity f ECs....
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...Bone orphogenic protein (BMP)-4, a member of the TGFuperfamily of cytokines (74), has recently been shown to be pregulated in ECs exposed to low and oscillatory ESS 7,101) (Fig....
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...Ultimately, low SS-mediated over-expression of growth promoters and nder-expression of growth inhibitors by the ECs stimulate SMCs to migrate from media to intima through a regionlly disrupted internal elastic lamina (IEL) (76,77)....
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References

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Journal Article•DOI•

Atherosclerosis — An Inflammatory Disease

[...]

Russell Ross¹•Institutions (1)

University of Washington¹

14 Jan 1999-The New England Journal of Medicine

TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.

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Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

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19,881 citations

Journal Article•DOI•

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

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Robert F. Furchgott¹, John V. Zawadzki¹•Institutions (1)

SUNY Downstate Medical Center¹

27 Nov 1980-Nature

TL;DR: It is demonstrated that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle.

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Abstract: Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.

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11,871 citations

Journal Article•DOI•

Atherosclerosis is an inflammatory disease

[...]

Russell Ross¹•Institutions (1)

University of Washington¹

01 Nov 1999-American Heart Journal

6,184 citations

Journal Article•DOI•

Vascular endothelial cells synthesize nitric oxide from L-arginine.

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Richard M.J. Palmer¹, D. S. Ashton, Salvador Moncada•Institutions (1)

Wellcome Trust¹

16 Jun 1988-Nature

TL;DR: It is demonstrated that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture and the strict substrate specificity of this reaction suggests that L- arginine is the precursor for NO synthesis in vascular endothelium cells.

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Abstract: Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue1 and for the inhibition of platelet aggregation2 and platelet adhesion3 attributed to endothelium-derived relaxing factor4. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay5, chemiluminescence1 or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.

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4,803 citations

Journal Article•DOI•

The pathogenesis of coronary artery disease and the acute coronary syndromes (1).

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Valentin Fuster¹, Lina Badimon, Juan J. Badimon, James H. Chesebro•Institutions (1)

Harvard University¹

23 Jan 1992-The New England Journal of Medicine

TL;DR: The two hypotheses to explain the pathogenesis of atherosclerosis, the "incrustation" hypothesis and the "lipid" hypothesis, are now known.

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Abstract: IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .

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3,779 citations